Damage to the central nervous system (CNS), either following injury or disease, is largely permanent and irreversible, mainly due to the limited capacity of the CNS for repair. The ability to treat CNS damage and promote CNS repair therefore represents a major area of unmet clinical need.
A key pathological hallmark of CNS damage is a change in the phenotype of astrocytes1. Astrocytes are defined by their stellar morphology, and expression of the glial fibrillary acidic protein (GFAP). They play an active role in organising brain structure and function2,3. After injury or disease, the astrocyte phenotype alters and acquires a state referred to as reactive astrocytosis3-5, in which it becomes enlarged, proliferates and changes shape. Numerous molecular pathways involving GFAP, vimentin and nestin as well as heparan sulphate proteoglycans (HSPGs), chondroitin sulphate proteoglycans and growth factors are altered4,6 Reactive astrocytosis is the key player in the formation of a glial scar, which is one of the most dramatic responses following injury and significantly hampers CNS repair3. The scar isolates areas of tissue damage and excludes non neural cells from the CNS parenchyma resulting from injury4. The search for the initial molecular inducer of inhibitory reactive astrocytosis is ongoing, but clearly, manipulating the astrocyte response to injury could lead to successful therapeutic strategies to enhance repair of CNS tissue.
Injury to the mammalian CNS often leads to a series of secondary events including death of local neurons, degeneration of axons, loss of myelin sheaths, initiation of an immune response and the formation of the glial scar by reactive astrocytes (astrocytosis). Due to these dramatic cellular events, the injury site is walled off by a scar and damage to non-functional tissue is generated; this is most apparent in spinal cord injury (SCI)7. One strategy being developed for CNS repair is glial cell transplantation, in which damaged tissue is grafted with cells that naturally support axonal regeneration and/or myelination7-9. This is a particularly strong strategy for repair of spinal cord injury, in which transplanted cells not only participate in repair but also bridge the gap in the damaged tissue to encourage axons to cross the injury site7-9. Many cell types have been studied, including glial cells, in particular, olfactory ensheathing cells (OECs, supporting glia in the olfactory system) and Schwann cells (SCs, supporting nerve glial cells). Both of these glial cell types can play a significant role in promoting axonal outgrowth and myelination after transplantation into a traumatic lesion. However, despite this profuse ingrowth of axons within the lesion, regenerating axons cannot cross the scar boundary formed in the host tissue at the lesion site.
There are also some important differences between OECs and SCs that might influence their selection for transplantation. This difference, which has been detected not only in vitro10,23, but also after transplantation in vivo, results in better integration of OECs than SCs with host astrocytes11,33.
It has been shown that OECs and SCs share many biological characteristics, including antigenic and morphological phenotypes and the ability to myelinate axons with peripheral-type myelin7,22,25,26. However, they interact differently with astrocytes, the main component of the glial scar24, in that SCs induce a reactive astrocyte phenotype, through which axons cannot regenerate40,46, whereas OECs do not10,11,23. This is in line with the native behaviour of OECs in the olfactory system where they intermix with astrocytes34,42. Studies have demonstrated that SCs and astrocytes form a boundary on contact and occupy distinct, non-overlapping areas10.
In contrast, OECs and astrocytes freely intermingle, without inducing a reactive astrocyte phenotype, although the addition of SC-conditioned medium (SCM) or heparin can induce SC-like behaviour in OECs. Furthermore, SCs will mingle with astrocytes if treated with an FGF receptor (FGFR) inhibitor, suggesting an involvement of heparan sulfate (HS)-dependent FGF signalling11.
Therefore, overall, of the two glial cell types studied, OECs have become a preferred candidate for transplantation due to their ability to evoke less of an astrocyte stress response10-12. However, the repair capacity of OECs may also be compromised by secreted factors from endogenous SCs invading the injury site when the blood brain barrier has been compromised13,14.
Accordingly, there is a need for improved approaches for promoting CNS repair in response to injury/damage.
There is also a need for improved approaches for preventing and/or treating reactive astrocytosis and glial scarring.
In addition, there is a need for improved glial transplantation strategies.